Prostate Cancer Prevention Trial (PCPT): Questions and Answers

In the Prostate Cancer Prevention Trial (PCPT), 30 percent fewer men taking the drug finasteride developed prostate cancer than men not taking the drug (10.5 percent of men on finasteride developed prostate cancer versus 14.9 percent of men not taking the drug after an average of 7 years). This reduction in risk was entirely from fewer low-grade cancers in men taking finasteride. Although men who developed prostate cancer while taking finasteride were more likely to have high-grade cancers, the increase was likely due, at least in part, to better detection of disease rather than being caused by the drug. An equal proportion of men in the finasteride group and in the placebo group were alive after 15 years (78 percent).

Background and Study Design

What was the Prostate Cancer Prevention Trial?
The PCPT was a study designed to see whether the drug finasteride (trade name Proscar) could prevent prostate cancer in men ages 55 and older. The study began in October 1993 at 221 sites across the United States. The PCPT was expected to continue until May 2004, but was stopped in June 2003 when an analysis showed that finasteride reduced the risk of developing prostate cancer by 25 percent. Additional analyses published in 2013 showed that with more followup, the risk of developing prostate cancer was reduced by about 30 percent (10.5 percent of men in the finasteride group versus 14.9 percent of men in the placebo group were diagnosed with prostate cancer).

The PCPT was funded by the National Cancer Institute (NCI), which gave $73 million in grants to the Southwest Oncology Group (SWOG). SWOG, a network of cancer researchers at medical centers around the United States, coordinated and carried out the trial.

In addition, Merck and Co., of Whitehouse Station, N.J., the manufacturer of finasteride, provided both the finasteride and the placebo without charge, and paid for distributing the pills to the study sites.

Who participated in the PCPT?
Men 55 years of age and older who were in good health and who showed no evidence of prostate cancer could enroll in the trial. Some 18,882 men joined the study over a recruitment period of three years.

Characteristics of the Participants:

Age: 31 percent were ages 55–59, 31 percent were 60–64, and 38 percent were ages 65 and older when they joined the study.

Race: 92 percent were white, 4 percent were African American, and 4 percent were from other racial and ethnic backgrounds.

Family history: 15 percent had a brother, father, or son who had prostate cancer.

How did the investigators know that the men did not have prostate cancer at the beginning of the study?
They didn't. However, men joining the trial had to have a digital rectal exam or DRE (where the doctor feels the prostate through the rectum to find hard or lumpy areas) that showed no sign of prostate cancer and a prostate-specific antigen, or PSA, blood level of 3.0 nanogram/milliliter (ng/mL) or less. PSA is a substance made by the prostate gland.

In 1993, when the PCPT began, men with a PSA level of 4.0 ng/mL or less were considered to be at very low risk of prostate cancer. To further reduce the chance that a man might enter the trial with an early, undiagnosed prostate cancer, a cutoff level of 3.0 ng/mL was chosen.

The best way to determine whether a man has prostate cancer is to examine cells from his prostate under a microscope. This can be done with a prostate biopsy, which involves removing small samples of prostate tissue with a needle and examining the samples under a microscope to check for cancer.

Did every man receive finasteride?
No. The PCPT was a randomized, placebo-controlledclinical trial. The men in the PCPT were randomized (selected by chance) to receive either finasteride or a placebo (an inactive pill that looks like finasteride). Half of the men in the study took finasteride, and half took a placebo. Neither the participant nor his PCPT physician knew which pill the participant was receiving. Setting up a study in this way allows researchers to determine the true benefits and side effects of an intervention (in this case, finasteride) without the influence of other factors such as the expectations of participants or researchers.

All men in the study were assigned to take one pill per day for up to seven years, either a 5 milligramdose of finasteride or a placebo.

How were the men monitored for side effects and for prostate cancer?
PCPT participants visited the study site twice a year and were contacted by phone twice a year to monitor their health and the occurrence of side effects. Participants were also asked to call the study site any time they had concerns or symptoms they thought might be related to the study.

Monitoring included a yearly physical exam, including a DRE and a PSA blood test. If a PSA screening or DRE suggested any problem, a prostate biopsy to check for cancer was recommended. Because finasteride lowers the level of PSA in the blood, a calculation was done to correct the reading, and the corrected number was used.

At the end of seven years in the study, each participant who had not been diagnosed with prostate cancer was asked to have a prostate biopsy. The biopsy involved using a needle to remove at least six small pieces of prostate tissue. The samples were then examined under a microscope to check for cancer. In the PCPT, these were called end-of-study biopsies. The initial analysis of the trial focused on the men who had been diagnosed with prostate cancer during the trial and men who had their end-of-study biopsies. The end-of-study biopsy was the best method to determine if a participant had prostate cancer.

When prostate cancer is diagnosed, how is it described?
Prostate cancer is described by both stage and grade. Stage refers to how far the cancer has spread, and grade describes how abnormal the tumor cells appear.

Stage: Early prostate cancer, stages I and II, has not spread outside the prostate gland. Stage III prostate cancer, often called locally advanced disease, extends outside the gland. Stage IV means the cancer has spread to other tissues or organs.

Grade: Based on the microscopic appearance of tumor tissue, pathologists may describe it as a low-, medium-, or high-grade cancer. The method most often used for grading prostate cancer is the Gleason system, which uses scores of 2 to 10. The pathologist studies samples of tissue from the prostate and grades the appearance of the tumor tissues on a scale of 1 to 5 to indicate how different they are from normal prostate tissue. The two most common grade patterns or the most common and the worst (most abnormal) grade patterns are added together to make a Gleason score. The higher the score, the higher the grade of the tumor. High-grade tumors (Gleason score 7–10) are more likely to grow quickly and spread beyond the prostate than lower-grade tumors. Gleason scores from biopsies give a preliminary assessment of overall grade because biopsies provide only a sample of the prostate tissue. Evaluation of the whole prostate after prostatectomy is the best assessment of tumor grade.

About Finasteride

What is finasteride and how does it work?
Finasteride is a drug that reduces levels of dihydrotestosterone (DHT) in the blood and the prostate gland. DHT is a male hormone that is important in normal and abnormal prostate growth. DHT plays a key role in noncancerous growth of the prostate (benign prostate enlargement or BPH) and is also involved in the development of prostate cancer. The prostate gland of men taking finasteride shrinks.

Finasteride works by blocking the action of an enzyme, 5-alpha reductase, which is needed to change the hormone testosterone into DHT. Finasteride has a chemical structure similar to the structure of testosterone, which lets it attach to 5-alpha reductase, making the enzyme unavailable to change testosterone to DHT.

In 1992, the U.S. Food and Drug Administration (FDA) approved the use of a 5 mg dose of finasteride, taken by mouth as a pill, for treating benign prostatic hyperplasia (BPH), a noncancerous enlargement of the prostate that can block the flow of urine. Finasteride is marketed as Proscar for this use. At a much lower dosage (1 mg), finasteride is used to prevent male pattern hair loss and promote hair growth and is marketed as Propecia.

Why was finasteride tested to prevent prostate cancer?
The development of prostate cancer is strongly influenced by male hormones. DHT in particular is known to promote the growth of prostate cells. Because finasteride inhibits the action of DHT, researchers believed the drug might prevent the cellular changes that can lead to prostate cancer without reducing their levels of testosterone. In support of this hypothesis, finasteride had already been shown to inhibit the growth of prostate cancer cells in laboratory experiments. Also, studies had shown that men with very low levels of 5-alpha reductase due to an inheriteddeficiency are not able to convert testosterone to DHT, and do not develop prostate cancer.

Can finasteride cause side effects?
Yes. Like most medications, whether over-the-counter drugs, prescription drugs, or drugs in medical studies, finasteride may cause side effects. Decreased sexual desire, impotence (difficulty achieving an erection), and decreased ejaculate volume are known side effects of this drug. There are treatments available that may lessen these side effects. Participants in the PCPT were regularly asked about side effects and were encouraged to call the study site any time they had concerns or symptoms they thought might be related to the study.

In the PCPT, men taking finasteride reported more sexual side effects than men on the placebo. However, men on finasteride were also less likely to experience urinary symptoms such as urgency/frequency of urination or incontinence and are less likely to need surgery for prostate enlargement

Study Results

What were the initial results of the PCPT published in 2003?
The PCPT was the first study to show that a drug can reduce a man's chances of developing prostate cancer. The initial evaluation, in 2003, showed that men randomized to take finasteride were 25 percent less likely to develop prostate cancers than men in the placebo group. This evaluation focused on the men who had their end-of-study biopsy or who had been diagnosed with prostate cancer during the study.

Almost all the prostate cancers in men on the PCPT were found in an early stage. Although men taking finasteride had fewer prostate cancers overall (18 percent of men in the finasteride group developed prostate cancer vs. 24 percent of men in the placebo group), there was an increase in high-grade disease among men in the finasteride arm (6.4 percent of men in the finasteride group vs. 5.1 percent of men in the placebo group). The absolute increase was only 1.3 percent, but it was statistically significant, meaning it was unlikely to be due to chance. High-grade tumors (Gleason score 7–10) are more likely to grow quickly and spread beyond the prostate than lower-grade tumors.

How did the investigators analyze long-term survival of PCPT participants?
For this analysis, published in the New England Journal of Medicine on August 15, 2013, investigators searched the Social Security Death Index through October 31, 2011, to determine how many men from the trial had died. The SSDI does not provide information on cause of death, so a separate analysis of the number of deaths due to prostate cancer could not be done. Researchers were also able to collect data on the incidence of prostate cancer in PCPT participants for an additional year after the first report was published in 2003, including data from men who did not have an end-of-study biopsy.

What did the long-term survival analysis of PCPT participants show?
For the men diagnosed with prostate cancer through June 2004, 10-year overall survival from when they were diagnosed was calculated, and was the same for men in the finasteride group (79.3 percent) and the men in the placebo group (79.5 percent). When survival was evaluated according to cancer grade at diagnosis, the 10-year survival rates for men with low-grade cancers was 83.0 percent (finasteride) and 80.9 percent (placebo). For high-grade cancers, the 10-year survival rates were 73.0 percent (finasteride) and 73.6 percent (placebo). This provides reassurance that the slight excess of higher grade tumors in the men in the finasteride arm of the study did not translate into an increased risk of death.

Likewise, after 15 years, overall survival of men from both groups (men with and without prostate cancer diagnoses) was equivalent: 78 percent of men in the finasteride group were still alive and 78.2 percent of men in the placebo group were still alive. The median age of PCPT participants at the time of this measure was 78.7 years.

What more do we know in 2013 about prostate cancers diagnosed in the PCPT?
Based on the one additional year of data about prostate cancer incidence, the 2013 analysis of PCPT data is in agreement with the initial study results. The 2013 analysis of PCPT participants showed that men who had taken finasteride developed about 30 percent fewer prostate cancers (989 of 9,423 or 10.5 percent ) than men in the placebo group ( 1,412 of 9,457 or 14.9 percent).

The difference in prostate cancer diagnoses was entirely due to fewer low-grade prostate cancers in the finasteride arm (Gleason score 2-6). There continued to be a slight increase in high-grade disease among men in the finasteride arm (333 of 9,423 or 3.5 percent ) versus men in the placebo arm (286 of 9,457 or 3 percent), but this difference is no longer statistically significant, and may be due to chance.

Did any group of men benefit more from finasteride than others?
The reduction in prostate cancer risk from finasteride was seen regardless of age, race/ethnicity, family history of prostate cancer, and PSA level at entry into the study. Research is in progress to determine whether a particular group of men would be more (or less) likely to benefit from finasteride based on other biological and molecular factors.

Other Concerns

Should men take finasteride to prevent prostate cancer?
Finasteride is not approved by the U.S. Food and Drug Administration for prevention of prostate cancer. Men with symptoms of BPH can talk to their health care provider about taking finasteride for this use.

Do other drugs that treat BPH have the same cancer prevention effect as finasteride?
The most commonly prescribed drugs for BPH are alpha blockers, including terazosin (sold as Hytrin), doxazosin (sold as Cardura), and tamsulosin (sold as Flomax). These drugs don't work in the same way as finasteride. Alpha blockers help BPH by relaxing the muscles in the prostate and neck of the bladder to allow better urine flow. They do not affect hormone levels the way finasteride does. It is unlikely that they would have an effect on prostate cancer risk, although these drugs have not been studied for this purpose.

The drug dutasteride (sold as Avodart) is also prescribed for BPH and works similarly to finasteride. The manufacturer of this drug began a study in 2004 called REDUCE (Reduction by Dutasteride of Prostate Cancer Events) in men with suspicious PSA levels and negative biopsies, who may be at increased risk for developing prostate cancer (ClinicalTrials.gov identifier: NCT00056407). In 2010, the study investigators reported that dutasteride reduced the risk of prostate cancer by 23 percent compared to men taking a placebo. Dutasteride is not approved by the U.S. FDA for prevention of prostate cancer.

Does Propecia prevent prostate cancer?
We don't know. The PCPT evaluated only the 5 mg dose of finasteride, not the 1 mg dose marketed as Propecia.

What proportion of men in the study was African American?
About 4 percent of the men in the PCPT were African American. PCPT investigators made strong efforts to invite African American men to participate in this trial, but participation was voluntary and investigators did not succeed in enrolling a large number of African Americans. Prostate cancer is a critical issue for African American men, who have the highest rates of this disease in the world. Finasteride was shown to be as effective in reducing prostate cancer risk among African American men as in men of other races.

Additional Research

What else has been found in the PCPT data about prostate cancer and finasteride since the trial ended?

Finasteride improves detection of prostate cancers. Finasteride has several effects on the prostate that allow better detection of prostate cancers. The drug shrinks the prostate, reducing its size and volume and increasing the chance that a biopsy will find existing cancers. This is true for all grades of prostate cancer, including high-grade disease. In addition, detection of overall cancers by DRE is also improved.

Men taking finasteride may not have a true increased risk of high-grade prostate cancer. Adjusting for the known effects that finasteride has on prostate cancer detection, investigators estimated that high-grade tumors (Gleason scores 7–10) were no more likely in the men taking finasteride than in the men taking placebo. However, because very few prostate cancers were detected at Gleason scores of 8 to 10, it is difficult to draw conclusions about this group.

Finasteride prevents cancer for which treatment would be recommended. Men receiving end-of-study biopsies in the PCPT would not have been diagnosed with prostate cancer outside of the trial. Some experts questioned if it was necessary to try to prevent them. Analysis of biopsy specimens from the PCPT indicates that the majority (75 percent) of all cancers in the PCPT and 60 percent of tumors with a Gleason score of 6 or less (the cancers finasteride is known to prevent) were found to be ‘clinically significant’, meaning that some doctors would recommend a patient receive treatment.

Finasteride decreases risk of a precursor to prostate cancer. One kind of microscopic change in the prostate known as high-grade prostatic intraepithelial neoplasia (PIN) may be a precursor to prostate cancer. Finasteride significantly decreased the overall risk of high-grade PIN in men in the PCPT at about the same rate that it decreased risk for prostate cancer.

Prostate cancer, including high-grade cancer, can be present even when PSA levels are 4.0 ng/mL or less. About 15 percent of men on placebo who had PSA levels of less than 4.0 ng/mL were found to have prostate cancer at the end-of-study biopsy. Of the men with prostate cancer, nearly 15 percent had tumors with a Gleason score of 7 or higher (2.3 percent of all the men who had an end-of-study biopsy). These results do not mean that the PSA level at which a physician recommends biopsy should be lowered, but rather highlight the difficulty of treating any PSA level as a yes/no test.

Additional materials and resources:

For more information on the prostate cancer prevention and treatment, call the NCI's Cancer Information Service at 1–800–4–CANCER (1–800–422–6237).